miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia

Abstract

HOXA9, and MEIS1 have essential oncogenic roles in mixed lineage leukaemia (MLL)-rearranged leukaemia. Here we show that they are direct targets of miRNA-196b, a microRNA (miRNA) located adjacent to and co-expressed with HOXA9, in MLL-rearranged leukaemic cells. Forced expression of miR-196b significantly delays MLL-fusion-mediated leukemogenesis in primary bone marrow transplantation through suppressing Hoxa9/Meis1 expression. However, ectopic expression of miR-196b results in more aggressive leukaemic phenotypes and causes much faster leukemogenesis in secondary transplantation than MLL fusion alone, likely through the further repression of Fas expression, a proapoptotic gene downregulated in MLL-rearranged leukaemia. Overexpression of FAS significantly inhibits leukemogenesis and reverses miR-196b-mediated phenotypes. Targeting Hoxa9/Meis1 and Fas by miR-196b is probably also important for normal haematopoiesis. Thus, our results uncover a previously unappreciated miRNA-regulation mechanism by which a single miRNA may target both oncogenes and tumour suppressors, simultaneously, or, sequentially, in tumourigenesis and normal development per cell differentiation, indicating that miRNA regulation is much more complex than previously thought.

Attenuation of microRNA-126 Expression That Drives CD34+38− Stem/Progenitor Cells in Acute Myeloid Leukemia Leads to Tumor Eradication

“…We found miR-125b, miR-10a, miR-196b, miR-551b, and miR-29b highly expressed in HSCs and to be decreased in AML, suggesting a potential role for these miRNAs in maintaining hematopoietic stem cell features such as self-renewal and/or therapy resistance. In fact, miR196b, miR-29b, and miR-125b have been shown to be involved in the formation of leukemia (27,43,44). Interestingly, miR-126 is highly expressed in HSCs and shows enhanced expression in LSCs compared with LPs, indicating a possible role for miR-126 in regulating hematopoietic as well as leukemic stem cell properties.…”

MiR‐139‐5p inhibits the tumorigenesis and progression of oral squamous carcinoma cells by targeting HOXA9

“…For instance, Li et al . detected that HOXA9 had essential oncogenic effect in leukaemia 29. Besides, Liu et al .…”

Identification of a 24-Gene Prognostic Signature That Improves the European LeukemiaNet Risk Classification of Acute Myeloid Leukemia: An International Collaborative Study

“…[1][2][3][4][5] Many gene expression profiling studies have been performed in AML using DNA microarrays, [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] and the results have proven to be valuable in diagnosis, classification, and prognosis. [22][23][24] However, gene signatures from different laboratories are not always consistent.…”